Indications, Detection, Completion and Retention Rates of Capsule Endoscopy in Two Decades of Use: A Systematic Review and Meta-Analysis

Background: Capsule endoscopy (CE) has become a widespread modality for non-invasive evaluation of the gastrointestinal (GI) tract, with several CE models having been developed throughout the years. The aim of this systematic review and meta-analysis is to evaluate performance measures such as completion, detection and retention rates of CE. Methods: Literature through to August 2021 was screened for articles regarding all capsule types: small bowel, double-headed capsule for the colon or PillCam®Crohn’s capsule, magnetically-controlled capsule endoscopy, esophageal capsule and patency capsule. Primary outcomes included detection rate (DR), completion rate (CR) and capsule retention rate (RR). DR, CR and RR were also analyzed in relation to indications such as obscure GI bleeding (OGIB), known/suspected Crohn’s disease (CD), celiac disease (CeD), neoplastic lesions (NL) and clinical symptoms (CS). Results: 328 original articles involving 86,930 patients who underwent CE were included. OGIB was the most common indication (n = 44,750), followed by CS (n = 17,897), CD (n = 11,299), NL (n = 4989) and CeD (n = 947). The most used capsule type was small bowel CE in 236 studies. DR, CR and RR for all indications were 59%, 89.6% and 2%, respectively. According to specific indications: DR were 55%, 66%, 63%, 52% and 62%; CR were 90.6%, 86.5%, 78.2%, 94% and 92.8%; and RR were 2%, 4%, 1%, 6% and 2%. Conclusions: Pooled DR, CR and RR are acceptable for all capsule types. OGIB is the most common indication for CE. Technological advancements have expanded the scope of CE devices in detecting GI pathology with acceptable rates for a complete examination.


Introduction
Since its introduction into clinical practice more than two decades ago [1], wireless capsule endoscopy (CE) has become an indispensable diagnostic modality for the small bowel (SB) due to its non-invasive nature. As a result, its diagnostic role has been expanded to include, apart from the investigation of obscure gastrointestinal bleeding (OGIB), that of inflammatory bowel disease (IBD), polyposis syndromes and celiac disease (CeD), among others. An infrequent but potentially serious adverse event is capsule retention. Although retention can be managed conservatively in most cases, occasionally it requires endoscopic or surgical intervention. Published capsule retention rates (RR) vary depending on the background indication [2,3] and the use of a patency capsule (PC), a radiopaque dissolvable capsule with an equivalent size and shape as its electronic counterpart. PC use has proven safe and efficient to accurately assess SB functional patency [4].
Furthermore, technological breakthroughs prompted the development of additional CE models to non-invasively evaluate other segments of the gastrointestinal (GI) tract. For example, with the release of the colon capsule endoscopy (CCE) (2006) and the PillCam ® Crohn's capsule (PCC) (2017) (which allows a pan-enteric exploration in a single procedure [5]), CE again disrupted GI diagnostics. Moreover, recent studies are looking into magnetically controlled capsules (MCCE) for gastric evaluation [6] or combined gastric and SB assessment [7]. Therefore, we aimed to perform a systematic review and meta-analysis of the available literature concerning lesion detection, examination completion and capsule RR for all commercially available capsule models (i.e., esophageal, gastric/MCCE, SB, CCE (or pan-enteric) and PC), based on procedure indications.

Search Strategy and Inclusion Criteria
Four of the authors (M.S., S.P., T.T., K.G.) independently searched PubMed/MEDLINE/ Embase/Ebsco/ClinicalTrials (from databases' inception until 17 August 2021) for studies presenting CE detection, completion and/or retention rates. We included studies that provided data on CEs performed in adults only, with study groups comprising at least 30 participants. We excluded reviews/systematic reviews, editorials/perspectives/opinion pieces, individual case reports, letters to editors/commentaries and study protocols. The search strings we used for each database are available in Appendix A. The electronic search was followed by a manual review of the reference lists of relevant systematic reviews. The study was registered at the PROSPERO international register of systematic reviews (ID: 311560).

Data Abstraction
We abstracted data on the study design, country, aims, patient groups (age, gender) and the type of capsule used according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard [8]. Next, we looked for data on CE indications and grouped them as OGIB, Crohn's disease (CD) (diagnostic workup or followup), neoplastic lesions (NL) or CeD. Other indications for CE that did not fit in any of the aforementioned groups are presented herein as clinical symptoms (CS). As the number of studies included in the final step exceeded 300, six independent investigators performed this step (A.E., M.S., S.P., M.R., T.T., K.G.). Capsule-type groups were defined as: capsule for the small bowel (SBCE), double-headed capsule for the colon (CCE) or PillCam ® Crohn's capsule (PCC), magnetically-controlled capsule endoscopy (MCCE), esophageal capsule (ESO) and patency capsule (PC). Whenever data were missing for the review, the authors of individual studies were contacted for additional information via email twice, two weeks apart. Consensus resolved any inconsistencies, with the last author/guarantor (A.K.) acting as adjudicator where necessary.

Outcomes
Primary outcomes were the rates of: (a) lesion detection (DR); (b) examination completion (CR); and (c) capsule retention. These were analyzed for specific indications and for all of the indications we evaluated. Outcomes were defined according to the definitions provided by the European Society of Gastrointestinal Endoscopy [9]; the definition of completion was based on the visualization of specific landmarks before the end of the recording: for SBCE procedures, imaging of the cecum; for CCE and PCC procedures, visualization of the anal verge/hemorrhoidal plexus; for ESO procedures, images of the stomach mucosa; for MCCE procedures, complete visualization of all anatomical gastric segments (i.e., cardia, fundus, body, incisura, antrum and pylorus). For PC procedures, completion was defined as either capsule excretion or radiological evidence of the capsule in the colon 30 h after ingestion.

Data Synthesis and Statistical Analysis
We conducted a random effects [10] model meta-analysis of outcomes when ≥3 studies contributed data using Comprehensive Meta-Analysis V3 (http://www.meta-analysis.com; last access 21 February 2022). Verification of abstracted data was performed by two separate investigators (A.S., A.L.). We explored study heterogeneity using the Chi-square test of homogeneity, with p < 0.05 indicating significant heterogeneity. All analyses were two-tailed with α = 0.05. The effect size that was measured was an event rate−in particular, DR, CR and RR. Subgroup analyses regarding the type of capsule were conducted. We conducted subgroup and exploratory maximum likelihood random effects meta-regression analyses of the co-primary outcomes, for all indication event rates. Meta-regression variables included: 1.
The year of publication (continuous moderator).

2.
The number of study participants (continuous moderator).

3.
The age of the participants (categorical moderator). We formulated the following ranges in the latter case: <60, 60-80 and >80 years old. Finally, we inspected funnel plots and used Egger's regression test [11] and the Duval and Tweedie's trim and fill method where applicable [12] to quantify whether publication bias could have influenced the results.

Search Results
The initial search yielded 3241 hits. Two thousand seven hundred thirty-five (n = 2735) studies were excluded after identification as duplicates and/or after evaluation on the title/abstract level. Subsequently, we did not identify other studies via hand search. Eventually, 506 full-text articles were reviewed. Of those, 178 were excluded due to not fitting our inclusion criteria. Reasons for exclusion were: type of study (case report, review, letter) (n = 28); too few participants (n = 30); age of the subjects included in the study (n = 11); animal studies (n = 2); language other than English/Spanish/French/Greek/Polish/Italian (n = 11); not enough data available (n = 30); full text not available (n = 35); technique presentation/diagnostic algorithms with no direct clinical CE involvement (n = 31). Therefore, 328 studies were found eligible and included in this meta-analysis (Supplementary Figure S1).

Study and Studied Subjects Characteristics
Altogether, 328 studies comprising 86,930 patients who underwent CEs were included in the final synthesis. We abstracted data from 122 retrospective and 206 prospective studies.
Patients of both genders were included, with the highest reported percentage of males being 94.2%. The youngest mean age was 26, while the highest median age was 72. The most prevalent indication for CE was OGIB (n = 44,750), followed by CD (n = 11,299), NL (n = 4989) and CeD (n = 947). Unspecified CS was reported in 17,897 individuals. The most used capsule type was SBCE in 236 studies ( Figure 1). Data are available in Supplementary Table S1.
full text not available (n = 35); technique presentation/diagnostic algorithms with no direct clinical CE involvement (n = 31). Therefore, 328 studies were found eligible and included in this meta-analysis (Supplementary Figure S1).

Study and Studied Subjects Characteristics
Altogether, 328 studies comprising 86,930 patients who underwent CEs were included in the final synthesis. We abstracted data from 122 retrospective and 206 prospective studies. Patients of both genders were included, with the highest reported percentage of males being 94.2%. The youngest mean age was 26, while the highest median age was 72. The most prevalent indication for CE was OGIB (n = 44,750), followed by CD (n = 11,299), NL (n = 4989) and CeD (n = 947). Unspecified CS was reported in 17,897 individuals. The most used capsule type was SBCE in 236 studies ( Figure 1). Data are available in Supplementary Table S1.

Lesion Detection Rates (DR) by Capsule Type
The DR was calculated per indication group as a pooled event rate. This was either provided by the authors (with no information regarding particular lesion types) or calculated by ourselves (as the sum of the detected lesions per indication group). In addition, we conducted a comparative analysis by capsule type. The DR for all lesions (pooled data) differed significantly by capsule type, with the highest rate for PCC (DR = 0.693), followed by CCE (DR = 0.643). However, in the indication subgroup analyses, there were no significant differences in DRs by capsule type; data is presented in Table 1. Raw data can be found in Supplementary Table S2

Lesion Detection Rates (DR) by Capsule Type
The DR was calculated per indication group as a pooled event rate. This was either provided by the authors (with no information regarding particular lesion types) or calculated by ourselves (as the sum of the detected lesions per indication group). In addition, we conducted a comparative analysis by capsule type. The DR for all lesions (pooled data) differed significantly by capsule type, with the highest rate for PCC (DR = 0.693), followed by CCE (DR = 0.643). However, in the indication subgroup analyses, there were no significant differences in DRs by capsule type; data is presented in Table 1. Raw data can be found in Supplementary Table S2. Exemplary forest plots (indication subgroup-OGIB and CD) are depicted in Figure 2 and Figure S2.

Completion Rates (CR) by Capsule Type
The CRs were also calculated per indication group as pooled event rates. The OGIB and CD subgroup analyses by capsule type demonstrated no significant differences in CRs. However, the CRs for NL, CS and pooled data differed significantly by capsule type, with the highest rates for CCE (NL: CR = 0.921; Supplementary Figure S3) and MCCE (CS: CR = 0.997; All indications: CR = 0.959). Data is presented in Table 2 and Table S3.

Retention Rates (RR) by Capsule Type
The RRs did not differ significantly by capsule types in the OGIB and CD indication groups. There were, however, significant differences for other indications. In the case of NL and CS, the lowest RRs were for PC (NL: RR = 0.002; CS: RR = 0.002; Supplementary Figure  S4), whilst for pooled indications, the lowest RRs were found for CCE (RR = 0.008) and MCCE (RR = 0.01). Data is presented in Table 3 and Supplementary Table S4

Discussion
This meta-analysis collected articles describing CE procedures in the last 20 years, focusing on specific performance indicators such as completion, detection and retention rates (Table 4). In 2010, Liao and colleagues [13] performed a systematic review with similar aims; however, they only extracted and analyzed SBCE outcomes because at that time, other CE literature was inevitably scarcer. Nevertheless, their work highlighted the acceptable SBCE safety profile and satisfactory pooled detection and CR of the analyzed studies. As technological advancements have allowed newer CE tools to enter the market, we decided that the time was ripe to provide a necessary, all-inclusive 2022 update by assimilating additional evidence in our analysis. Although several other monothematic meta-analyses have been published to date, including a detailed meta-analysis on adverse events for all types of CE by the same group [14]. This work provides a detailed overview of the entire spectrum of CE use in clinical practice. Our analysis showed no significant difference in the pooled lesion detection per indication group in CE, although the highest DRs were seen with PCC and CCE. This overarching result supports published studies that advocate for routine use of doubleheaded CE in SB assessment, largely due to its enhanced detection potential and ability to change clinical diagnosis and patient management [15]. Naturally, CD and NL were the indication group with the highest DR, with percentages of 66% and 63%, respectively. One explanation for this could be a more selective allocation in these patient groups and the expected higher incidence of colonic neoplasia when compared to SB NL.
Overall, completion was obtained in 89.6% of the procedures (all types of CE), in line with previous results in the literature [13]. OGIB and CD, the most represented indications, did not show any statistically significant difference in CR (90.6% and 86.5%, respectively), or even in the subgroup analyses per capsule type. CCE was used in the investigation of colonic NL in 11 studies, with a satisfactory CR of over 92%. Retention, probably the most cumbersome adverse event in CE, is an uncommon complication (<1% of the procedures), which is known to be reduced by the use of PC [14] and favored by underlying CD [3]. In our study, the overall RR was as low as 2%, with the highest values of 4% and 6% in CD and CeD, respectively. The highest values seen in CeD can likely be explained by heterogeneity due to the low number of studies (only 6) compared to other indications (68, 52, 50 and 23, respectively, for OGIB, CS, CD and NL).
This study has a number of limitations. First, the heterogeneity of the included studies in regard to the terminology of measured outcomes and data presentation, with publication bias (shown by Egger's tests) on outcomes of CRs and RRs. Secondly, the exclusion of studies with <30 participants may add uniformity to the results while excluding potentially useful data from the analysis. Last, the meta-regression was performed at a study level, thereby not allowing further analyses on the demographical data.

Conclusions
In conclusion, in the last 20 years, CE has confirmed its substantial role in GI examination. With an excellent safety profile, technological advancements have expanded the scope of CE devices in the detection of GI pathology with acceptable rates for complete examination; however, pitfalls still persist (e.g., capsule retention in CD patients, optimal and shared bowel preparation regimens). It is expected that the widespread adoption of AI-based technologies, which provide high profiles of pathology detection and characterization, will further enhance the performance outcomes of CE [16].

Conflicts of Interest:
A.K. has the following declarations to make-Co-founder of AJM MED-I-CAPS Ltd.; co-director of iCERV Ltd.; Consultancy fees from Jinshan Ltd.; travel support from Jinshan, Aquilant, and DrFalkPharma; research support (grant) from ESGE/Given Imaging Ltd. and (material) IntroMedic/SynMed; honoraria from DrFalkPharmaUK, Ferring and Jinshan. Consultancy in Advisory board meetings for Dr FalkPharma UK, Tillots, ANKON. E.T. has the following declarations to make -Medtronic and Olympus (consultancy fee), Ankon (study material).

Appendix A
Search terms used per database are described below: For PubMed/MEDLINE/Ebsco: (capsule endoscopy OR capsule endoscopy OR capsule enteroscopy OR wireless capsule endoscopy OR wireless capsule enteroscopy OR capsule endoscope OR capsocam OR capsocam plus OR capsocam sv-1 OR capsocam sv1 OR endocapsule OR imaging m2a capsule OR m2a (capsule endoscope) OR mirocam OR mirocam green OR mirocam mc 1600 OR mirocam mc2000 OR mirocam navi OR mirocam system OR omom OR omom capsule endoscopy system OR pillcam OR pillcam colon OR pillcam colon 2 OR pillcam eso OR pillcam sb OR capsule endoscope OR capsule endoscopes OR video capsule endoscopy system OR video capsule endoscopy system capsule OR video capsule endoscopy system transmitter OR wireless capsule endoscope) AND (detection OR completion OR retention OR aspiration OR aspirate) NOT (review OR review OR meta-analysis OR analysis, meta OR meta-analysis OR meta-analysis OR meta-analysis). Filter applied: Humans.